Alcohol and cancer.

Epidemiological data have identified chronic alcohol consumption as a significant risk factor for upper alimentary tract cancer, including cancer of the oropharynx, larynx and the oesophagus and of the liver. The increased risk attributable to alcohol consumption of cancer in the large intestine and in the breast is much smaller. However, although the risk is lower, carcinogenesis can be enhanced with relatively low daily doses of ethanol. Considering the high prevalence of these tumours, even a small increase in cancer risk is of great importance, especially in those individuals who exhibit a higher risk for other reasons. The epidemiological data on alcohol and other organ cancers is controversial and there is at present not enough evidence for a significant association. Although the exact mechanisms by which chronic alcohol ingestion stimulates carcinogenesis are not known, experimental studies in animals support the concept that ethanol is not a carcinogen but under certain experimental conditions is a cocarcinogen and/or tumour promoter. The metabolism of ethanol leads to the generation of acetaldehyde (AA) and free radicals. Evidence has accumulated that acetaldehyde is predominantly responsible for alcohol associated carcinogenesis. Acetaldehyde is carcinogenic and mutagenic, binds to DNA and proteins, destructs folate and results in secondary hyperproliferation. Acetaldehyde is produced by tissue alcohol hydrogenases, cytochrome P 4502E1 and through bacterial oxidative metabolism in the upper and lower gastrointestinal tract. Its generation or its degradation is modulated due to functional polymorphisms of the genes coding for the enzymes. Acetaldehyde can also be produced by oral and faecal bacteria. Smoking, which changes the oral bacterial flora, and poor oral hygiene also increase acetaldehyde. In addition, cigarette smoking and some alcoholic beverages such as calvados contain acetaldehyde. Other mechanisms by which alcohol stimulates carcinogenesis include the induction of cytochrome P-4502E1, which is associated with an enhanced production of free radicals and enhanced activation of various procarcinogens present in alcoholic beverages; in association with tobacco smoke and in diets, a change in the metabolism and distribution of carcinogens; alterations in cell cycle behaviour such as cell cycle duration leading to hyperproliferation; nutritional deficiencies, such as methyl-, vitamin E-, folate-, pyridoxal phosphate-, zinc- and selenium deficiencies and alterations of the immune system eventually resulting in an increased susceptibility to certain virus infections such as hepatitis B virus and hepatitis C virus. In addition, local mechanisms may be of particular importance. Such mechanisms lead to tissue injury such as cirrhosis of the liver, a major prerequisite for hepatocellular carcinoma. Also, an alcohol-mediated increase in oestradiols may be at least in part responsible for breast cancer risk. Thus, all these mechanisms functioning in concert actively modulate carcinogenesis leading to its stimulation.

Acute hepatitis induced by Greater Celandine (Chelidonium majus).

We report on two cases of acute liver injury along with the intake of Greater Celandine (Chelidonium majus), a well-known herbal remedy frequently used for irritable bowel syndrome. All other possible causes of acute liver damage were excluded in both patients. In one patient, cholestatic hepatitis recurred rapidly after involuntary re-exposition. Both patients fully recovered after the withdrawal of Greater Celandine. The two cases add to the existing database about the potential hepatotoxicity of drugs containing Greater Celandine and raise the question whether the approval of this drug should be re-evaluated in the light of lacking evidence for a therapeutic benefit.

[Alcohol and the liver]. / Alkohol und Leber.

Since ethanol metabolism predominantly takes place in the liver it is not surprising that hepatic intermediary metabolism is strikingly influenced. Alcohol is metabolized via three enzyme systems: alcohol dehydrogenase (ADH), microsome ethanol oxidizing system (MEOS) and catalase. The ADH reaction produces reducing equivalents as NADH which results in various metabolic disorders such as hyperproteinemia IV and V, hypoglycaemia, lactacidosis, hyperuricaemia, and certain forms of porphyria. The metabolism of hormones is also disturbed. Alcohol fatty liver is a direct consequence of NADH production. Alcoholic liver disease comprises of fatty liver, alcoholic hepatitis and cirrhosis. Risk factors of alcoholic liver disease are the amount of alcohol consumed, drinking pattern, female gender and certain genetic predispositions. Alcoholic hepatitis is characterized by a typical clinical and laboratory feature, and specific heaptic morphology. Poor prognostic factors are continuous alcohol consumption, cholestatis and perivenular fibrosis. Alcoholic cirrhosis has similar complications as cirrhosis of other etiology. Therapy includes abstinence, antioxidative drugs, steroids, and S-adenosylmethionine. Liver transplantation is of long-term benefit.

Additive effect of nitric oxide inhalation on the oxygenation benefit of the prone position in the adult respiratory distress syndrome.

BACKGROUND: The response to inhaled nitric oxide and prone positioning was investigated in 47 patients with adult respiratory distress syndrome to test the hypothesis that inhalation of nitric oxide when in the prone position would result in additive improvement in oxygenation. METHODS: The authors prospectively studied patients of both genders who were 15 to 75 yr old and had adult respiratory distress syndrome confirmed by computed tomography (lung injury score, 3.1+/-1). RESULTS: Compared with baseline values in the supine position (T1), inhalation of 10 ppm nitric oxide for 1 h (T2) decreased the mean pulmonary artery pressure from 33+/-9 mmHg to 28+/-6 mmHg (P < 0.05; T2 vs. T1) and increased the ratio of the partial pressure of oxygen in arterial blood (PaO2) to inspired oxygen concentration (FiO2) from 115 (median first quartile [Q1] 97, median third quartile [Q3] 137) to 148 (Q1 132, Q3 196) (P < 0.05; T2 vs. T1). Cessation of nitric oxide brought the values back to baseline (T3). Two hours of prone positioning (T4) significantly increased the PaO2:FiO2 ratio (T4 vs. T3). However, after an additional hour of nitric oxide inhalation in the prone position (T5), a significant decrease of the venous admixture (from 33+/-6% to 25+/-6%; P < 0.05) and an increase of the PaO2:FiO2 ratio (from 165 [Q1 129, Q3 216] to 199 [Q1 178, Q3 316] [P < 0.05; T5 vs. T4]) were observed. CONCLUSIONS: In patients with isolated severe adult respiratory distress syndrome, inhalation of nitric oxide in the prone position significantly improved oxygenation compared with nitric oxide inhalation in the supine position or in the prone position without nitric oxide. The combination of the prone position with nitric oxide inhalation in the treatment of severe adult respiratory distress syndrome should be considered.

Alcohol and cancer.

A great number of epidemiological data have identified chronic alcohol consumption as a significant risk factor for upper alimentary tract cancer, including cancer of the oropharynx, larynx, and the esophagus, and for the liver. In contrast to those organs, the risk by which alcohol consumption increases cancer in the large intestine and in the breast is much smaller. However, although the risk is lower, carcinogenesis can be enhanced with relatively low daily doses of ethanol. Considering the high prevalence of these tumors, even a small increase in cancer risk is of great importance, especially in those individuals who exhibit a higher risk for other reasons. The epidemiological data on alcohol and other organ cancers are controversial and there is at present not enough evidence for a significant association. Although the exact mechanisms by which chronic alcohol ingestion stimulates carcinogenesis are not known, experimental studies in animals support the concept that ethanol is not a carcinogen, but under certain experimental conditions is a cocarcinogen and/or (especially in the liver) a tumor promoter. The metabolism of ethanol leads to the generation of acetaldehyde and free radicals. These highly reactive compounds bind rapidly to cell constituents and possibly to DNA. Acetaldehyde decreases DNA repair mechanisms and the methylation of cytosine in DNA. It also traps glutathione, an important peptide in detoxification. Furthermore, it leads to chromosomal aberrations and seems to be associated with tissue damage and secondary compensatory hyperregeneration. More recently, the finding of considerable production of acetaldehyde by gastrointestinal bacteria was reported. Other mechanisms by which alcohol stimulates carcinogenesis include the induction of cytochrome P4502E1, associated with an enhanced activation of various procarcinogens present in alcoholic beverages, in association with tobacco smoke and in diets, a change in the metabolism and distribution of carcinogens, alterations in cell cycle behavior such as cell cycle duration leading to hyperregeneration, nutritional deficiencies such as methyl, vitamin A, folate, pyrridoxalphosphate, zinc and selenium deficiency, and alterations of the immune system, eventually resulting in an increased susceptibility to certain viral infections such as hepatitis B virus and hepatitis C virus. In addition, local mechanisms in the upper gastrointestinal tract and in the rectum may be of particular importance. Such mechanisms lead to tissue injury such as cirrhosis of the liver, a major prerequisite for hepatocellular carcinoma. Thus, all these mechanisms, functioning in concert, actively modulate carcinogenesis, leading to its stimulation.

Cytokine patterns in patients who undergo hemofiltration for treatment of multiple organ failure.

The excessive uncontrolled activation of inflammatory cells and mediators after trauma or major surgery plays a key role in the development of adult respiratory distress syndrome and multiple organ system failure (MOSF). In the past elevated cytokine levels were shown to influence the outcome of these patients adversely. There are diverging results regarding the removal of circulating cytokines by various methods of hemopurification for clinical improvement of MOSF. Seven patients after trauma or major surgery underwent continuous venovenous hemofiltration (CVVH) for the treatment of severe organ failure of the heart and lungs (Murray score 2.74) but not for renal or liver failure. The cytokine levels were measured at the beginning and 15, 60, 120, and 240 minutes after initiation of CVVH (measure points MP1-5). Clinical improvement during the treatment was monitored, and correlation with cytokine levels was evaluated. Arterially measured tumor necrosis factor alpha rose from 11.14 ng/ml to 17.86 ng/m1 (p < 0.05). Arterial interleukin-6 (IL-6) levels significantly decreased during CVVH from 1284.7 ng/m1 to 557.9 ng/m1; IL-8 levels simultaneously decreased from an initial peak of up to 154.4 ng/m1 at MP3 to 97.3 ng/m1 at MP5. The drop in serum IL-6 and IL-8 levels closely correlated with clinical improvement. After 2 hours of CVVH the hemodynamic situation improved significantly, as revealed by a decrease in catecholamine expenditure, an increase in arterial pressure, and a decrease in pulmonary artery pressure. Moreover, 2 hours after the initiation of CVVH the oxygenation index rose significantly and correlated well with the drop in shunt fraction. The Murray score significantly fell to 1.86. The removal of IL-6 and IL-8 by CVVH after initial stimulation correlates with clinical improvement, which was demonstrated by significantly improved oxygenation and hemodynamics from 2 hours after the initiation of CVVH onward. The elimination of cytokines and several mediators by CVVH may contribute to the cardiopulmonary improvement of critically ill patients. In comparison with the clinical control group (n = 7), which was comparable in terms of MOSF, no intervention led to a similar improvement in cardiorespiratory failure, and overall two of these patients died. Moreover, patients of the control group experienced a significant longer stay at in the intensive care unit.

The role of gastrointestinal factors in alcohol metabolism.

Although the liver is the major organ responsible for ethanol metabolism, such metabolism also occurs in the gastrointestinal (GI) tract. However, compared to the liver, GI metabolism of ethanol is quantitatively much lower. Various enzyme systems have been characterized in GI mucosal cells including various isozymes of alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP 2E1) and catalase. Gastric ADH activity is one factor by which first pass metabolism (FPM) is influenced and its activity is modulated by genetics, gender, age, drugs and gastric morphology. Another important factor in FPM of ethanol is the speed of gastric emptying. In addition to mucosal ethanol metabolism, ethanol can also be oxidized by many bacterial species in the upper GI tract including oropharynx and stomach as well as in the large intestine. GI metabolism of ethanol may influence systemic bioavailability of ethanol and may lead to local toxicity most likely mediated by acetaldehyde. Such toxicity could be of importance in ethanol-associated carcinogenesis.

Alcohol and gastrointestinal cancer: pathogenic mechanisms.

Chronic heavy alcohol consumption leads to a significantly increased risk of cancer in the oropharynx, larynx and the oesophagus. In the liver, chronic alcohol abuse results in cirrhosis, a precursor of hepatocellular cancer. More recentepidemiologic studies also demonstrate that regular alcohol consumption, even in low amounts, has an enhanced risk for rectal cancer and cancer of the breast. Alcohol by itself is not a carcinogen. However, alcohol can increase the susceptibility of various organs to chemical carcinogens by a variety of mechanisms. Among these, increased activation of procarcinogens through microsomal enzyme induction, a change in the metabolism and/or distribution of carcinogens, interference with the system that repairs carcinogen-induced DNA alkylations, direct mucosal tissue damage with consecutive stimulation of cellular regeneration and alcohol-mediated malnutrition may be of importance. In the upper gastrointestinal tract the production of acetaldehyde and free radicals via cytochrome P450 2E1 and via alcohol dehydrogenase may lead to tissue damage and to secondary hyper-regeneration. In addition, local mechanisms may also be involved in the co-carcinogenic process. In the rectal mucosa acetaldehyde seems to be an important factor in carcinogenesis and may be predominantly produced by faecal bacteria.

Complications after emergency tube thoracostomy: assessment with CT.

PURPOSE: To assess the spectrum of complications after emergency tube thoracostomy (TT) and show the role of computed tomography (CT) in detection of these abnormalities. MATERIALS AND METHODS: CT scans, chest radiographs, and clinical data were reviewed in 51 patients (77 tubes) who underwent emergency TT after trauma. CT scans were analyzed for chest tube malposition (CTM) and persistent pneumo- or hemathoraces. RESULTS: The complication most often seen after emergency TT, as demonstrated with CT, was CTM (20 of 77 tubes [26%]). Only seven of the CTMs seen at CT were evident on chest radiographs. Two extrathoracic and 18 intrathoracic (five intraparenchymal, nine intrafissural) malpositioned tubes were seen at CT. Other findings included persistent pneumo-and hemathoraces in 16 patients. CONCLUSION: Patients undergoing emergency TT are at increased risk for complications. CTM is the most common abnormality and should be diagnosed promptly to prevent additional problems. CT is more useful than plain radiography for establishing a diagnosis.

Respiratory burst capability of polymorphonuclear neutrophils and TNF-alpha serum levels in relationship to the development of septic syndrome in critically ill patients.

Activated polymorphonuclear neutrophils (PMN) and neutrophil activating mediators such as tumor necrosis factor-alpha (TNF-alpha) are thought to be involved in the pathophysiology of sepsis and multiple organ failure syndrome (MOFS). In critically ill patients at high risk for the development of septic syndrome (n = 17) peripheral blood PMN were assayed for O2- and H2O2 production after stimulation with phorbol myristate acetate (PMA, 40 nM). Serum TNF-alpha levels were determined by ELISA. At the time of admission to the intensive care unit we found significant higher levels of TNF-alpha (P = 0.0001) in the serum of patients finally developing sepsis correlating to higher respiratory burst capability in comparison to nonseptic patients. Additionally we were able to demonstrate a significant (P = 0.0016) lower dismutation rate of O2- to H2O2 in deceased patients in comparison to survivors. These results give further evidence that elevated levels of circulating TNF-alpha and activated PMN play a significant role in the pathogenesis of septic syndrome in critically ill patients.

[Is TNF-alpha "ripe" for routine diagnosis in sepsis?]. / Ist TNF-alpha "reif" für die Routinediagnostik in der Sepsis?

Mortality of the septic syndrome is around 40-60% and can rise to 100% if multiple organ failure (MOF) develops. It is generally assumed that the high mortality of sepsis can only be reduced by early diagnosis and prevention of subsequent MOF. The aim of our study was to investigate the validity of routine TNF-alpha determination for the diagnosis of septicemia and, in combination with clinical scoring systems [MOF score and Acute Physiological and Therapeutic Intervention Score (APATIS)], to define a "therapeutic window" during which an anti-TNF-alpha agent could be applied with the greatest chance of success. METHODS. TNF-alpha serum levels were measured and APATIS and MOF scores were calculated daily in 87 ICU patients. TNF-alpha serum levels were determined by means of an immunoradiometric assay (TNF-alpha IRMA, Medgenix, Belgium). Sepsis was diagnosed in 24 patients according to clinical criteria. To quantify the severity of sepsis, we set up the APATIS. The MOF score was used to assess the severity of MOF. Data were analyzed using the SAS software package (SAS Institute, Cary, N.C.) and are expressed as mean +/- SEM. RESULTS. The mean values of all sequential TNF-alpha determinations were significantly higher in the septic patients compared to the nonseptic patients (73.2 +/- 4.3 vs 8.5 +/- 0.4 pg/ml; P less than 0.01). Similarly, the maximum TNF-alpha values were significantly higher in the septic group (156.9 +/- 26.5 vs 20.1 +/- 1.3 pg/ml; P less than 0.01). To differentiate between sepsis and nonsepsis we set the cut-off point at a TNF-alpha serum level of 40 pg/ml and calculated a sensitivity of 70.8%, a specificity of 98%, and a diagnostic accuracy of 91.3%. None of the patients with a maximum TNF-alpha level above 250 pg/ml survived. Mortality was 80% above a maximum TNF-alpha serum concentration of 200 pg/ml, whereas only 40% of patients with a TNF-alpha maximum below 150 pg/ml died. The mean APATIS and MOF scores were significantly higher for septic than for nonseptic patients (APATIS: 20.3 +/- 0.5 vs 8.1 +/- 0.2 and MOF: 9.8 +/- 0.1 vs 4.6 +/- 0.1). To differentiate between survival and nonsurvival, we set the cut-off point at 25 for APATIS and calculated a sensitivity of 79% and a specificity of 93%. At a MOF score of 8, the sensitivity was 89% and the specificity 82%. In our series cumulative mortality at a maximum MOF of less than 8 was 4% and at MOF greater than 10, 68%. We found an interval of 2.9 +/- 0.9 days between the time TNF-alpha serum levels first exceeded 40 pg/ml and the development of severe MOF (MOF greater than 10) in 13 patients. CONCLUSION. Sequential TNF-alpha serum level determinations are useful for the diagnosis and prognosis of septicemia. We found an interval of 3 days between rising TNF-alpha serum levels and the development of severe MOF. This latency may represent the "therapeutic window" during which an anti-TNF-alpha-agent, e.g., a monoclonal anti-TNF-alpha-antibody, could be applied as a therapeutic consequence.